Na,K-β – a master chaperone for ion transporters and adhesion molecules
Date
2015
Authors
Journal Title
Journal ISSN
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Publisher
University of Delaware
Abstract
Cell membranes are enriched with a variety of proteins that play various roles in
maintaining cell architecture and function. Structural and functional integrity of
epithelial cells are maintained by synergistic interaction between adherent and tight
junctions. Extensive studies have been carried out to understand the architecture of
these complexes and the signal transducers that aid in maintaining the morphology of
epithelia. Na,K-ATPase is a very well established membrane protein involved in
maintaining ion homeostasis by mediating [Na+] efflux and formation of tight
junctions. It is a hetero-oligomer with a catalytic α-subunit (Na,K-α) and a regulatory
β-subunit (Na,K-β). Historically, Na,K-β was identified as a chaperone for the
transport and stabilization of its cognate partner Na,K-α (Geering, 1997). Na,KATPase
expression governs intracellular Na+ and Ca2+ concentration thus assisting the
formation and maintenance of tight junctions, governing epithelial polarity
(Rajasekaran et al., 2001b). Further studies have reported that Na,K-β functions
synergistically with well-known cell adhesion molecule, E-cadherin regulating
epithelial architecture. Moreover Na,K-β plays an important role in cell-cell adhesion
and suppression of cell motility (Barwe et al., 2005; Rajasekaran et al., 2001b;
Shoshani et al., 2005; Tokhtaeva et al., 2011; Vagin et al., 2006). In my study, I
explore the molecular basis of the functional synergism between E-cadherin and
Na,K-β, and provide evidence that Na,K-β associates with E-cadherin and regulates its
membrane localization, acting as a chaperone (Chapter 2).
Recent studies have demonstrated that Na,K-β is a binding partner essential
for membrane localization of other ion transporters apart from Na,K-α. 1) Na,K-β
interacts and targets the transport of large conductance Ca2+ activated K+ channels
(BKCa) to specific regions of plasma membrane (Jha and Dryer, 2009) and also 2)
Na,K-β regulates Na,K,2Cl co-transporter (NKCC2) channel exocytosis and
membrane expression (Carmosino et al., 2014). Though Na,K-α is known to
functionally couple with Na+, Ca2+ exchanger 1 (NCX1), the role of Na,K-β in the
regulation of membrane expression of NCX1 remained unexplored. My study focused
on elucidating the role of Na,K-β in governing NCX1 expression. The results indicate
that Na,K-β mediates membrane trafficking of NCX1 that is required for suppression
of Ca2+-dependent epithelial cell migration (Chapter 3) (Balasubramaniam et al.,
2015b).
Taken together these studies suggest that in addition to its auxiliary role in
aiding the trafficking of these proteins, Na,K-β also stabilizes their membrane
expression. The stabilization of these proteins at the membrane is essential for their
steady-state expression and function. These interesting observations suggest the
collaboration of ion transporters and adhesion proteins regulate the epithelial
phenotype. Loss of Na,K-β expression has been associated with EMT that leads to
cancer progression and renal fibrosis (Rajasekaran et al., 1999; Rajasekaran et al.,
2010). My study indicates that the loss of Na,K-β involves the changes in the
expression and function of other membrane proteins, in addition to having a direct
correlation between expression and cancer prognosis. Thus it can be inferred that
during the loss of Na,K-β in pre-neoplastic lesions, a plethora of events are unleashed
by downregulation of adhesion molecules and ion transporters, culminating in cancer.